ESPE Abstracts

MYRF is known to regulate the myelination of the central nervous system and mice with a conditional deletion of MYRF in oligodendrocyte precursors has anomalies of motor skill. Recently, several loss-of-function and missense mutations in MYRF have been reported in association with syndromic forms of congenital heart disease (CHD) with elements of Scimitar syndrome and/or with congenital diaphragmatic hernia (CDH). In most 46,XY individuals a range of urogenital anomalies were reported.

In an exome screen of 240 individuals with 46,XY DSD we identified three children with loss-of-function mutations in MYRF and one individual with a novel, predicted deleterious, missense mutation. The first case consisted of a 46,XY female who presented with primary amenorrhea at 14 yrs with female external genitalia, uterus and gonads located in the pelvis. Gonadotropins were elevated and testosterone levels were low. She was diagnosed with 46,XY partial gonadal dysgenesis. She carried a novel loss-of-function mutation involving an essential splice side c.2572+1G>A in MYRF. The second case consisted of a 46,XY boy with ambiguous external genitalia and hypogonadism. Histology of the gonads indicated a testis-like structure with absence of Leydig cells suggesting Leydig cell hypoplasia. He carried a novel missense mutation c.A313G:p.N105D in MYRF that was predicted to be damaging to the protein by multiple predictive software. A third child, who presented at birth with ambiguous external genitalia and inguinal testis and was raised as a female. The karyotype was 46,XY. Histology of both the left and right testis revealed tubule structures with Sertoli cells but with the complete absence of Leydig cells indicating Leydig cell hypoplasia. Exome sequencing revealed a de novo frameshift mutation c.2831_2835del:p.N944fs*51 in MYRF. The fourth case was a 46,XY girl who presented at birth with ambiguity of the external genitalia, minor cardiac anomalies and CDH. Histology of the gonads indicated Leydig cell hypoplasia. Exome sequencing revealed a de novo frameshift mutation c.2270delG:p.S725fs*64.

All four mutations are absent from public databases including gnomAD and in two of the children, where DNA of the parents was available for study, the mutation was found to be present only in the affected child. In three of the four children, there was no evidence of any other somatic anomalies. These data indicate that mutations in MYRF are associated with both syndromic and non-syndromic forms of 46,XY partial gonadal dysgenesis and 46,XY Leydig cell hypoplasia.